Diffuse large B-cell lymphoma displays striking heterogeneity at clinical, genetic and molecular levels. The International Prognostic Index is useful to predict the outcome of diffuse large B-cell lymphoma patients. However, patients with identical International Prognostic Index values in clinical practice exhibit marked variability in survival, suggesting the presence of significant residual heterogeneity within each category. Since cytokines such as interleukin-6, -8 and -10 play important roles in the pathogenesis of lymphomas, and plasma level of beta2-microglobulin is associated with the outcome of patients with diffuse large B-cell lymphoma, the aim of the present study was to determine whether these parameters combined with the International Prognostic Index would better stratify these patients to predict their prognosis.
Patients and Methods
The study included 46 untreated diffuse large B-cell lymphoma patients.
Results
All study parameters (International Prognostic Index, Ann Arbor stage, extra-nodal involvement, performance status, lactate dehydrogenase, beta2-microglobulin, interleukin-6 and -10, and response to therapy) except for patient age and serum interleukin-8 level were associated with overall survival. In addition, the International Prognostic Index was strongly correlated with beta2-microglobulin, interleukin-6, -8 and -10, and when combined these parameters significantly better stratified patients according to survival. On multivariate analysis, therapeutic response to the primary treatment, elevated interleukin-6 and -10 levels, and the International Prognostic Index were significant predictors of overall survival.
Conclusions
Our data imply that interleukins and beta2-microglobulin evaluation should be used in association with the International Prognostic Index to define prognostic subgroups in diffuse large B-cell lymphoma patients.
MooreD.F.Jr., CabanillasF.: Overview of prognostic factors in non-Hodgkin's lymphoma.Oncology (Williston Park),12(10 Suppl 8): 17–24, 1998.
2.
LossosI.S., MorgenszternD.: Prognostic biomarkers in diffuse large B-cell lymphoma.J Clin Oncol, 24: 995–1007, 2006.
3.
KurzrockR.: Cytokine deregulation in cancer.Biomed Pharmacother, 55: 543–547, 2001.
4.
SallesG., CoffierB.: Inherited cytokine response and risk of lymphoma.Lancet Oncol, 7: 3–4, 2006.
5.
Van SnickJ.: Interleukin-6: an overview.Annu Rev Immunol, 8: 253–257, 1990.
6.
HuangS., RobinsonJ.B., DeguzmanA., BucanaC.D., FidlerI.J.: Blockade of nuclear factor-kappa B signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin-8.Cancer Res, 60: 5334–5339, 2000.
7.
InoueK., SlatonJ.W., KimS.J., PerrotteP., EveB.Y., Bar-EliM., RadinskyR., DinneyC.P.: Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer.Cancer Res, 60: 2290–2299, 2000.
8.
MooreK.W., de Waal MalefytR., CoffmanR.L., O'GarraA.: Interleukin-10 and the interleukin-10 receptor.Annu Rev Immunol, 19: 683–765, 2001.
9.
O'GarraA., StapletonG., DharV., PearceM., SchumacherJ., RugoH., BarbisD., StallA., CuppJ., MooreK.: Production of cytokines by mouse B-cells: lymphomas and normal B-cells produce interleukin 10.Int Immunol, 2: 821–832, 1990.
10.
ContastaI., PellegriniP., BerghellaA.M., AdornoD.: Cell cycle control in cellular homeostasis during the immune response: interactions between Th1, Th2 cytokines, and bcl2 and p53 molecules.Cancer Biother Radiopharmaceut, 16: 63–71, 2001.
11.
SantosM., CleversH., de SousaM., MarxJ.J.: Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in b2-microglobulin knockout mice.Blood, 91: 3059–3065, 1998.
12.
AlbitarM., VoseJ.M., JohnsonM.M., DoK.A., DayA., JilaniI., KantarjianH., KeatingM., O'BrienS.M., VerstovsekS., ArmitageJ.O., GilesF.J.: Clinical relevance of soluble HLA-I and beta2-microglobulin levels in non-Hodgkin's lymphoma and Hodgkin's disease.Leuk Res, 31: 139–145, 2006.
13.
HarrisN.L., JaffeE.S., DieboldJ., FlandrinG., Muller-HermelinkH.K., VardimanJ., ListerT.A., BloomfieldC.D.: The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissue: report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997.Histopathology, 36: 69–87, 2000.
14.
CarboneP.P., KaplanH.S., MushoffK., SmithersD.W., TubianaM.: Report of the Committee on Hodgkin's Disease Staging Classification.Cancer Res, 31: 1860–1861, 1971.
15.
OkenM.M., CreechR.H., TormeyD.C., HortonJ., DavisT.E., McFaddenE.T., CarboneP.P.: Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol, 5: 649–655, 1982.
16.
HermansJ., KrolA.D., van GroningenK., KluinP.M., Kluin-NelemansJ.C., KramerM.H., NoordijkE.M., OngF., WijermansP.W.: International prognostic index for aggressive non-Hodgkin's lymphoma is valid for all malignancy grades.Blood, 86: 1460–1463, 1995.
17.
ChesonB.D., HorningS.J., CoiffierB., ShippM.A., FisherR.I., ConnorsJ.M., ListerT.A., VoseJ., Grillo-LópezA., HagenbeekA., CabanillasF., KlippenstenD., HiddemannW., CastellinoR., HarrisN.L., ArmitageJ.O., CarterW., HoppeR., CanellosG.P.: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group.J Clin Oncol, 17: 1244–1253, 1999.
18.
Duletić-NačinovićA., ŠtifterS., DvornikS.: Correlation of serum IL-6, IL-8 and IL-10 levels with clinicopathological features and prognosis in patients with diffuse large B-cell lymphoma.Int J Lab Hematol, 30: 230–249, 2008.
19.
KhouriI.F., SalibaR.M., OkorojiG.J., AcholonuS.A., ChamplinR.E.: Long-term follow-up of autologous stem cell transplantation in patients with diffuse mantle cell lymphoma in first disease remission: the prognostic value of beta2-microglobulin and the tumor score.Cancer, 98: 2630–2632, 2003.
20.
RabanN., GiraudeauB., DesablensB., SensebeL., DelwailV., FoussardCh, LamyTh, DugayJ., ReisenleiterM., RodonPh, GauvinJ.B., ColombattPh: VECP-Bleo regimen as treatment of advanced stage aggressive non-Hodgkin's lymphoma in elderly patients: a GOELAMS protocol.Hematol Cell Ther, 42: 142–148, 2000.
21.
BettiniR., CaronniF., MainoC., MarzettaK., SalaD., SaccaV., GoriniM.: Validity of the Internatonal Prognostic Index in non-Hodgkin's lymphomas of varying grades of malignancy.Recenti Prog Med, 94: 494–500, 2003.
22.
SavageK.J., Al-RajhiN., VossN., PaltielC., KlasaR., GascoyneR.D., ConnorsJ.M.: Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience.Ann Oncol, 17: 123–130, 2006.
23.
HsuS.M., WaldronJ.W.Jr., HsuP.L., HoughA.J.Jr.: Cytokines in malignant lymphomas: review and prospective evaluation.Hum Pathol, 24: 1040–1057, 1993.
24.
Lech-MarandaE., BaseggioL., BienvenuJ., CharlotC., BergerF., RigalD., WarzochaK., CoiffierB., SallesG.: Interleukin-10 gene promoter polymorphisms influence the clinical outcome of diffuse large B-cell lymphoma.Blood, 103: 3529–3534, 2004.
25.
StasiR., ZinzaniP.L., GalieniP., LautaV.M., DamasioE., DispensaE., DammaccoF., PapaG., TuraS.: Clinical implications of cytokines and soluble receptor measurements in patients with newly-diagnosed aggressive non-Hodgkin's lymphoma.Eur J Haematol, 54: 9–17, 1995.
26.
AydinF., YilmazM., OzdemirF., KavgaciH., YavuzM.N., YavuzA.A.: Correlation of serum IL-2, IL-6 and IL-10 levels with international prognostic index in patients with aggressive non-Hodgkin's lymphoma.Am J Clin Oncol, 25: 570–572, 2002.
27.
BlayJ.Y., BurdinN., RoussetF., LenoirG., BironP., PhilipT., BanchereauJ., FavrotM.C.: Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor.Blood, 82: 2169–2174, 1993.
28.
CortesJ., KurzrockR.: Interleukin-10 in non-Hodgkin's lymphoma.Leuk Lymphoma, 26: 251–259, 1997.
29.
SeymourJ.F., TalpazM., CabanillasF., WetzlerM., KurzrockR.: Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma.J Clin Oncol, 13: 373–382, 1995.
30.
PretiH.A., CabanillasF., TalpazM., TuckerS.L., SeymourJ.F., KurzrockR.: Prognostic value of serum interleukin-6 in diffuse large-cell lymphoma.Ann Intern Med, 127: 186–194, 1997.
31.
SerebriakovN.B., NovikA.A., ShamanskiiS.V., KrivolapovIuA, VoloshinS.V., D'IakovaV.V., SnetkovaI.G., KatkovaI.V., ZhiburtE.B.: Diagnostic and prognostic value of interleukin-6 in malignant non-Hodgkin's lymphomas.Vestn Ross Akad Med Nauk, 10: 32–36, 1998.
32.
PedersenL.M., KlausenT.W., DavidsenU.H., JohnsenH.E.: Early changes in serum IL-6 and VEGF levels predict clinical outcome following first-line therapy in aggressive non-Hodgkin lymphoma.Ann Hematol, 84: 510–516, 2005.
33.
Duletić-NačinovićA., Sever-PrebiliićM., ŠtifterS., JonjićN., HasanM., LabarB.: Interleukin-6 in patients with aggressive and indolent non-Hodgkin's lymphoma: a predictor of prognosis?Clin Oncol,18: 367–368, 2006.
34.
El-FarM., FoudaM., YahyaR., el-BazH.: Serum IL-10 and ILt diagnosis as independent predictors of outcome in non-Hodgkin's lymphoma.J Physiol Biochem, 60: 253–258, 2004.
35.
Duletić-NačinovićA., Sever-PrebilićM., JonjićN.: Prognostic value of interleukin-6 in lymphoma patients (abstract).Hematol J,3(Suppl 1): 275, 2002.
36.
RetzlaffS., PadróA.T., KochP., OelmannE., LügeringN., MestersR.M., BerdelW.E.: Interleukin 8 and Flt 3 ligand as markers of advanced disease in primary gastrointestinal non-Hodgkin's lymphoma.Oncol Rep, 9: 525–527, 2002.
37.
StasiR., ZinzaniL., GalieniP., LautaV.M., DamasioE., DispensaE., DammaccoF., TuraS., PapaG.: Detection of soluble interleukin-2 receptor and interleukin 10 in the serum of patients with aggressive non-Hodgkin's lymphoma. Identification of a subset at high risk of treatment failure.Cancer, 74: 1798–1800, 1994.
38.
Lech-MarandaE., BienvenuJ., MichalletA.S., HouotR., RobakT., CoiffierB., SallesG.: Elevated IL-10 plasma levels correlate with poor prognosis in diffuse large B-cell lymphoma.Eur Cytokine Netw, 17: 60–66. 2006.
